Nearly 20 million Americans were illicit drug users in 2005, of which 7 million were classified with substance dependence or abuse (2005). The economic burden to society is substantial, estimated to be $180 billion reflecting costs related to health care, loss of productivity, crime, and social welfare (2004). Evidence that repeated exposure to drugs alters neural function and cellular morphology (Kalivas and Volkow, 2005;Volkow and Li, 2004) has led to the hypothesis that the transition from experimentation to addiction involves disruption of neural circuits, namely cortico-limbic and cortical-striatal systems, that mediate drive, motivation, and decision making. The long term objective of this proposal is to understand the neurobiological mechanisms underlying impaired judgment and risky decision-making in substance dependent individuals. A laboratory task of decision making administered to substance dependent individuals (SDI) and other patient populations is the Iowa Gambling Task (IGT) (Bechara et al., 1994). This task emulates the uncertainties of gains and losses encountered in real life. Patients with prefrontal cortex lesions characteristically make risky decisions choosing immediate reward in the face of long term loss and are markedly impaired on the IGT. SDI make similar risky decisions in real life and show impaired performance on this task, supporting a role for abnormal prefrontal function in SDI. Specifying the mechanism for such decision making characteristics on the IGT has been difficult, in part, because i) the task is confounded on its payoff schedule, ii) a neurally-specific conceptual framework of decision making has been lacking, and iii) the inferior prefrontal cortex is difficult to image with MR methods due to susceptibility artifact. We propose a modified gambling task (mGT) that addresses the confounded pay-off schedule, has been tested in a neural-based cognitive model of decision making (Frank and Claus, 2006), and will be coupled with a partial z-shim MR technique to maximize visualization of medial and orbitofrontal lobe. We will study SDI and healthy controls to address 2 specific aims: Aim 1. Determine if there is lower orbitofrontal (OFC) activity during decision-making in SDI compared to controls on a modified gambling task (mGT). Aim 2. Determine if risky decisions made by SDI are mediated by reduced orbitofrontal activity during decisions that reflect magnitude of gains or punishment. PUBLIC HEALTH RELEVANCE This proposal is relevant to public health because of the considerable costs incurred by drug abuse in this country. Compared to research on other chronic diseases, addiction research receives limited attention by the community due to the stigma attached to it and limited resources from the pharmaceutical industry because of low reimbursement. Understanding the neural substrates of impaired decision making processes, however, may identify vulnerable groups and will help guide therapy. [unreadable] [unreadable] [unreadable]